The Clinical Efficacy of Clopidogrel Bisulfate Tablets Combined with Olmesartan Medoxomil for Ischemic Stroke with Hypertension and the Effect of Angiotensin II Type 1 Receptor Level on Prognosis.

BACKGROUND: Ischemic stroke combined with hypertension can increase risks of stroke recurrence and death. AIM: The aim of this study is to investigate the clinical efficacy of clopidogrel bisulfate tablets combined with olmesartan medoxomil in the treatment of ischemic stroke patients with hypertension and the effect of angiotensin II type 1 receptor (AT1R) level on prognosis. METHODS: Ninety ischemic stroke patients with hypertension were chosen for continuous treatment with clopidogrel bisulfate tablets and olmesartan medoxomil for 12 months. The Modified Edinburgh Scandinavian Stroke Scale (MESSS) score, Brunnstrom score, Barthel score, death, recurrence, and progression of cerebrovascular residual lesions were observed and recorded during the treatment period. According to the plasma AT1R expression of the patients before treatment, the patients were divided into a high-AT1R group and low-AT1R group. Then, survival analysis was performed. RESULTS: Compared with pretreatment, the MESSS scores of the patients at the first, second, third, sixth, ninth, and twelfth months after treatment were reduced (p < 0.01) while the Brunnstrom score and Barthel score were prominently boosted (p < 0.01). Compared with the low-AT1R group, patients in the high-AT1R group had higher rates of stroke recurrence and progression of residual cerebrovascular lesions (p < 0.05). CONCLUSION: Clopidogrel bisulfate tablets combined with olmesartan medoxomil has prominent clinical effects in the treatment of ischemic stroke patients with hypertension, evidently improving the prognosis. In addition, the level of AT1R may be a vital factor affecting the prognosis.

Visualisation of real-time oral biodistribution of fluorescent labeled self-microemulsifying drug delivery system of olmesartan medoxomil using optical imaging method.

In the present study, the biodistribution of self-microemulsifying drug delivery system of hydrophobic olmesartan medoxomil (OM-SMEDDS) was determined by labeling with a fluorescent dye VivoTag®680 XL and Xenolight® DiR. Labeled OM-SMEDDS and control dye solution administered orally to mice; real-time dynamic biodistributions over 7 h were determined by 2D-fluorescent imaging to verify their anatomic location. Fluorescent Emissions by Vivotag 680® XL and Xenolight® DiR labeled OM-SMEDDS emitted 2 to 24 times stronger emission than control dye administered group. To further confirm the results, organs were removed and examined using the same technique at the end of 7 h. VivoTag®680XL and Xenolight® DiR emitted 4 and 1.7 times stronger emission respectively than control dye administered mice in ex-vivo organ imaging studies. This study showed that OM-SMEDDS can be succesfully labeled with fluorescent dye and tracked with optical imaging method for the visualisation of biodistribution of drugs and is also useful for enhanced bioavailability.

Formulation of lyophilized oily-core poly-Ɛ-caprolactone nanocapsules to improve oral bioavailability of Olmesartan Medoxomil.

Objective: This study aims to detect the enhancement in the oral bioavailability of a poorly water-soluble antihypertensive drug Olmesartan Medoxomil (OM) due to the formulation of lyophilized oily-core nanocapsules.Significance: A comparative pharmacokinetic study in rats was conducted for oily-core polymeric nanocapsules (ONC) after formulation and lyophilization against market tablet products to show the significant improvement in oral absorption of OM.Materials and methods: OM loaded ONC were prepared using poly-Ɛ-caprolactone (0.5% w/v) as a polymer and an oily core of Labrafac PG® by applying a well-controlled nanoprecipitation technique in terms of injection rate (80 mL/h) and magnetic stirring rate (300 rpm). The prepared lyophilized ONC were in-vitro characterized after reconstitution and evaluated in-vivo for oral bioavailability after a single OM oral dose (20 mg/kg) of reconstituted lyophilized ONC dispersion was administered to rats.Results: The prepared lyophilized ONC containing 10% w/v mannitol showed an average particle size of 158 nm, polydispersity index of 0.37, negative zeta potential value equals 33.9 and entrapment efficiency of 90%. The dissolution profile for OM from lyophilized ONC powder filled into hard gelatin capsules (HGC) showed a 1.8-fold increase in dissolution rate as compared to the pure drug. In-vivo pharmacokinetic study in rats revealed a significant enhancement in the oral bioavailability of OM with 1.6-fold increase for AUC0-24 and a 1.9-fold increase for Cmax as compared to marketed product.Conclusion: It is concluded that the formulation of lyophilized ONC for OM can significantly enhance its oral bioavailability and consequently, its therapeutic efficacy and patient compliance.

Tailoring of PEGylated bilosomes for promoting the transdermal delivery of olmesartan medoxomil: in-vitro characterization, ex-vivo permeation and in-vivo assessment.

INTRODUCTION: The intention of this work was to load olmesartan medoxomil (OLM), a sparsely water soluble antihypertensive bioactive with low oral bioavailability (26%), into PEGylated bilosomes (PBs) for augmenting its transdermal delivery. PBs contain PEGylated single chain edge activator besides the components of traditional bilosomes (Span 60, cholesterol and bile salts). The PEG gives further resilience to vesicle membrane and is speculated to augment both permeability and bioavailability of OLM. METHODS: A 24 factorial experiment was constructed to inspect the impact of diverse variables on vesicles' features and sort out the optimal formula adopting Design Expert® software utilizing thin film hydration technique. Vesicles' evaluation was done by finding out entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and amount of drug released after 6 hrs (Q6h). The optimal formula was selected and characterized for further investigations. RESULTS: The optimal formula (PB15) showed spherical vesicles with EE% of 72.49±0.38%, PS of 559.30±10.70 nm, PDI of 0.57±0.15, ZP of -38.35±0.65 mV and Q6h of 59.60±0.24%. PB15 showed higher deformability index (28.39±5.71 g) compared to traditional bilosomes (5.88±0.90 g) and transethosomes (14.94±0.63 g). Further, PB15 showed superior skin permeation from rat's skin relative to the drug suspension. Moreover, confocal laser scanning microscopy examination revealed efficient penetration of the fluoro-labeled PB15 through skin. Histopathological study ensured the safety of PB15. In addition, in-vivo skin deposition studies showed higher OLM deposition in rat's skin from PB15 compared to transethosomes and OLM suspension. Furthermore, pharmacodynamic and pharmacokinetic studies performed using male Wistar rats and male Albino rabbits, respectively, showed the superiority of PB15 over oral tablets. PB15 was found to have significantly higher AUC0-48 and AUC0-∞ relative to the oral tablets. As well, the relative bioavailability of PB15 was found to be 235.04%. CONCLUSION: Overall, the obtained results confirmed the creditable effect of PB15 for transdermal delivery.

In Vitro and In Vivo Evaluation of Olmesartan Medoxomil Microcrysta ls and Nanocrystals: Preparation, Characterization, and Pharmacokinet ic Comparison in Beagle Dogs.

BACKGROUND: Olmesartan medoxomil (OLM) is a promising prodrug hydrolyzed to olmesartan (OL) during absorption from the gastrointestinal tract. OL is a selective angiotensin II receptor antagonist, with high drug resistance and low drug interaction. However, OLM has low solubility and low bioavailability. Therefore, it is extremely urgent to reduce the drug particle size to improve its biological bioavailability. OBJECTIVE: The aim of the study was to improve the oral bioavailability of poorly water-soluble olmesartan medoxomil (OLM) by using different particle size-reduction strategies. METHOD: Raw drug material was micronized or nanosized by either jet or wet milling processes, respectively. The particle sizes of the prepared nanocrystals (100-300 nm) and microcrystals (0.5-16 µm) were characterized by DLS, SEM, and TEM techniques. Solid state characterization by XPRD and DSC was used to confirm the crystalline state of OLM after the milling processes. RESULTS: We demonstrated that OLM nanocrystals enhanced solubility and dissolution in the non-sink condition in which high sensitivity was found in purified water. After 1 h, 65.4% of OLM was dissolved from nanocrystals, while microcrystals and OLMETEC® only showed 37.8% and 31.9% of drug dissolution, respectively. In the pharmacokinetic study using Beagle dogs, an increase in Cmax (～2 fold) and AUC (～1.6 fold) was observed after oral administration of OLM nanocrystals when compared to microcrystals and reference tablets, OLMETEC®. In contrast, OLM microcrystals failed to improve the oral bioavailability of the drugs. CONCLUSION: Particles size reduction to nano-scale by means of nanocrystals technology significantly increased in vitro dissolution rate and in vivo oral bioavailability of OLM.

Use of transethosomes for enhancing the transdermal delivery of olmesartan medoxomil: in vitro, ex vivo, and in vivo evaluation.

INTRODUCTION AND AIM: Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability due to extensive first-pass metabolism. This study aimed to prepare transetho somes (TEs) for enhancing the transdermal delivery of OLM to avoid its oral problems. METHODS: TE formulae were prepared utilizing 51.31 full factorial design using various surfactants (SAAs) and different phospholipid-to-SAA ratios. The formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and the amount of drug released after 6 hours (Q6h). Design Expert® software was employed to select the optimum formula. RESULTS: The optimum formula (TE14) had an EE% of 58.50%±1.30%, PS of 222.60±2.50 nm, PDI of 0.11±0.06, ZP of -20.80±0.30 mV, and Q6h of 67.40%±0.20%. In addition, TE14 was compared to transferosomes (TFs) in terms of elasticity and was found to show higher deformability index. Further, evaluation of ex vivo permeation using both rat and shed snake skin showed higher permeability of TE14 compared to TFs and OLM suspension. Confocal laser scanning microscopy confirmed the capability of the fluorolabeled TE14 to penetrate deep within the skin, while the histopathological study confirmed its safety. TE14 successfully maintained normal blood pressure values of rats up to 24 hours. Moreover, TE14 showed superiority in dermatokinetic study when compared with drug suspension. CONCLUSION: Taken together, the obtained results confirmed the potential of employing TEs as a successful carrier for the transdermal delivery of OLM.

Inhibition of Co-Crystallization of Olmesartan Medoxomil and Hydrochlorothiazide for Enhanced Dissolution Rate in Their Fixed Dose Combination.

Olmesartan medoxomil (Olm) and hydrochlorothiazide (HCTZ) are fixed dose combination (FDC) for treatment of hypertension. They have hydrogen bonding sites and may interact during co-processing. The consequences of such interaction are not clear. This study investigated the possibility of this interaction during co-processing. The research was extended to inhibit deleterious interactions. The drugs were co-evaporated from ethanolic solution to maximize the chance of interaction. This was performed in the absence and presence of hydroxypropyl methylcellulose (HPMC) and/or aerosil. The products were characterized using Fourier transform infrared spectroscopy (FTIR), differential thermal analysis, and powder X-ray diffraction (PXRD) in addition to dissolution studies. Co-evaporation of Olm with HCTZ in the absence of excipients produced crystalline material with FTIR spectrum showing intermolecular hydrogen bonding. This material showed thermal pattern of new crystalline species. This was identified as Olm/HCTZ co-crystal by PXRD. This co-crystallization reduced the dissolution rate of both drugs. This co-crystallization was inhibited in the presence of HPMC, but the dissolution rate was not significantly enhanced accordingly. Co-processing in the presence of both HPMC and aerosil eliminated the co-crystallization and minimized the intermolecular drug-drug interaction with subsequent dissolution enhancement. The study introduced a composition for fixed dose combination of Olm and HCTZ with enhanced dissolution.

Probable interacción entre Olmesartán y Rosuvastatina por inhibición de OATP1B1 / No disponible

No disponible

Fabrication of Nanosuspension Directly Loaded Fast-Dissolving Films for Enhanced Oral Bioavailability of Olmesartan Medoxomil: In Vitro Characterization and Pharmacokinetic Evaluation in Healthy Human Volunteers.

Olmesartan medoxomil (OM) is an antihypertensive drug with poor water solubility and low oral bioavailability (28.6%). Accordingly, this study aimed to formulate and evaluate OM nanosuspension incorporated into oral fast-dissolving films (FDFs) for bioavailability enhancement. OM nanosuspension was prepared by antisolvent-precipitation-ultrasonication method and characterized regarding particle size (122.67 ± 5.03 nm), span value (1.40 ± 0.51), and zeta potential (- 46.56 ± 1.20 mV). Transmission electron microscopy (TEM) of the nanosuspension showed spherical non-aggregating nanoparticles. The nanosuspension was then directly loaded into FDFs by solvent casting technique. A full factorial design (22 × 31) was implemented for optimization of the FDFs using Design-Expert® software. Physical and mechanical characteristics in addition to dissolution profiles of the FDFs were investigated. The optimum formula (FDF1) showed 0.43 ± 0.02 kg/mm2 tensile strength, 20.50 ± 2.12 s disintegration time, and 87.53 ± 2.50 and 95.99 ± 0.25% OM dissolved after 6 and 10 min, respectively. Accelerated and long-term shelf stability studies confirmed the stability of FDF1. More than 75% OM was dissolved within 10 min from FDF1 compared with 9.80 and 47.80% for films prepared using coarse drug powder and market tablet, respectively. Relative bioavailability of FDF1 compared to market tablet was assessed in healthy human volunteers. The Cmax value increased significantly from 66.62 ± 14.95 to 179.28 ± 23.96 ng/mL for market tablet and FDF1, respectively. Similarly, the AUC0-72 value significantly increased from 498.36 ± 217.46 to 1083.67 ± 246.32 ng h/mL for market tablet and FDF1, respectively. Relative bioavailability of FDF1 was 209.28%. The highlighted results verified the effectiveness of OM nanosuspension-loaded FDFs in improving OM bioavailability.

Long-term efficacy and tolerability of azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide in chronic kidney disease.

An open-label, long-term study evaluated safety and tolerability of azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs olmesartan/hydrochlorothiazide (OLM/HCTZ) in hypertensive participants with stage 3 chronic kidney disease. Initial therapy was AZL-M/CLD 20/12.5 mg (n = 77) or OLM/HCTZ 20/12.5 mg (n = 76), but could be up-titrated (AZL-M/CLD to 40/25 mg; OLM/HCTZ to 40/25 mg [US] or 20/25 mg [Europe]) with other agents added during weeks 4-52. Primary endpoint was proportion of participants with ≥ 1 adverse event (AE) through week 52. Baseline demographics were similar. AEs did not differ between groups (88.3%, AZL-M/CLD vs 76.3%, OLM/HCTZ; P = .058). AZL-M/CLD showed greater systolic BP reductions after initial dosing (P = .037) but not during long-term follow-up (P = .588). A greater proportion of participants up-titrated to the highest dose with OLM/HCTZ (48.7%) vs AZL-M/CLD (29.9%) (P = .021) and were taking additional antihypertensive medications (26.3% vs 16.9%). Both AZL-M/CLD and OLM/HCTZ showed similar efficacy and tolerability.

Solid lipid nanoparticles as an efficient drug delivery system of olmesartan medoxomil for the treatment of hypertension.

The aim of the current investigation was to develop solid lipid nanoparticles of olmesartan medoxomil using hot homogenization method to improve its oral bioavailability. Central composite design was applied to optimize the formulation variables; lipid X1 (Glyceryl monostearate) and surfactant X2 (Poloxamer: Tween 80). The particle sizes were in the nanometer range and spherical shaped for all prepared solid lipid nanoparticles formulations and the zeta potential absolute values were high, predicting good long-term stability. In vitro study of olmesartan loaded solid lipid nanoparticle exhibited controlled release profile for at least 24 h. The rate and extent of drug diffusion was studied using dialysis sac, rat's stomach and intestine tissues; study demonstrated that drug release from the solid lipid nanoparticles was significantly higher than drug suspension. In vivo pharmacokinetic study of olmesartan loaded solid lipid nanoparticles revealed higher Cmax of 1610 ng/mL, higher AUC of 15492.50 ng/mL and increased relative bioavailability by almost 2.3 folds compared to marketed formulation. These results clearly indicate that olmesartan loaded solid lipid nanoparticles are shown to have enhanced bioavailability and effective therapeutic result and thus would be an excellent way to treat hypertension. Hence, these solid lipid nanoparticles could represent as a great potential for a possible alternative to conventional oral formulation in the treatment of hypertension.

Comparison of long-term safety of fixed-dose combinations azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide.

This 52-week, randomized, open-label study evaluated long-term safety/tolerability of fixed-dose combination azilsartan medoxomil/chlorthalidone (AZL-M/CLD) vs fixed-dose combination olmesartan medoxomil/hydrochlorothiazide (OLM/HCTZ) in patients with essential hypertension (stage 2; clinic systolic blood pressure 160-190 mm Hg). Initial AZL-M/CLD 40/12.5 mg/d (n=418) or OLM/HCTZ 20/12.5 mg/d (n=419) could be uptitrated during weeks 4 to 52 (AZL-M/CLD to 80/25 mg; OLM/HCTZ to 40/25 mg [United States] or 20/25 mg [Europe]) to meet blood pressure targets. Treatment-emergent adverse events/serious adverse events occurred in 78.5%/5.7% of patients taking AZL-M/CLD vs 76.4%/6.2% taking OLM/HCTZ. The most frequent adverse events were dizziness (16.3% vs 12.6%), blood creatinine increase (21.5% vs 8.6%), headache (7.4% vs 11.0%), and nasopharyngitis (12.2% vs 11.5%). Hypokalemia was uncommon (1.0% vs 0.7%). Greater blood pressure reductions with AZL-M/CLD by week 2 were maintained throughout the study, despite less uptitration (32.3% vs 48.9% with OLM/HCTZ). Fixed-dose combination AZL-M/CLD showed an encouraging benefit-risk profile when used per standard clinical practice in a titrate-to-target strategy.

Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S-Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects.

PURPOSE: A fixed-dose combination (FDC) pill of amlodipine (relatively old calcium channel blocker as dihydropyridine) and olmesartan (relatively new angiotensin II receptor blocker) is used for hypertension that is not adequately controlled with a single-formulation drug. Because the FDC is a one-pill formulation, and amlodipine and olmesartan have different mechanisms of action, it is expected to improve patients' medication compliance and have an increased blood pressure-lowering efficacy. The purpose of this study was to assess the safety profile and the bioequivalence of two different FDC formulations [amlodipine besylate/olmesartan medoxomil 10/40 mg (reference product) and S-amlodipine nicotinate/olmesartan medoxomil 5/40 mg (test product)]. METHODS: A randomized, open-label, single-dose, 2-treatment, 2-way, and 2-period crossover study, including a 3-week washout period, was performed in 32 healthy Korean male volunteers. To analyze the concentration of S-amlodipine or olmesartan, plasma samples were collected up to 144 hours after the dose for S-amlodipine and 48 hours after the dose for olmesartan. Pharmacokinetic parameters, including the Cmax and the area under the curve from time 0 to the last measurable concentration (AUC0-last) for the time versus concentration plot, were calculated. Analysis of variance for bioequivalence was conducted using Cmax and AUC0-last converted to log scale, and the mean ratios and 90% CIs were determined. Safety data included analysis of adverse events (AEs), vital signs, physical examinations, clinical laboratory test, and 12-lead ECGs. FINDINGS: Of the 32 enrolled participants, 29 healthy volunteers completed the study. For both S-amlodipine and olmesartan, the main pharmacokinetic parameters were all within the acceptable range for regulatory bioequivalence. The 90% CIs for the geometric mean ratios of Cmax and AUC0-last were 0.8766 to 0.9760 and 0.8288 to 0.9224, respectively, for S-amlodipine and 0.9097 to 1.1229 and 0.8904 to 1.0407, respectively, for olmesartan. Hypotension was the most frequent AE, and it was observed in 4 volunteers with the test product and 7 volunteers with the reference product. Both the test and reference formulations were well tolerated. IMPLICATIONS: The present study demonstrates that the newly developed FDC product (test drug) and the conventional FDC product (reference drug) have comparable pharmacokinetic characteristics in healthy adult male volunteers. Both the test and reference products indicated good tolerance in this population, and no serious AEs were observed.

Development of olmesartan medoxomil optimized nanosuspension using the Box-Behnken design to improve oral bioavailability.

The aim of the present investigation was to enhance the oral bioavailability of olmesartan medoxomil by improving its solubility and dissolution rate by preparing nanosuspension (OM-NS), using the Box-Behnken design. In this, four factors were evaluated at three levels. Independent variables include: concentration of drug (X1), concentration of surfactant (X2), concentration of polymer (X3) and number of homogenization cycles (X4). Based on preliminary studies, the size (Y1), zeta potential (ZP) (Y2) and % drug release at 5 min (Y3) were chosen as dependent responses. OM-NS was prepared by high pressure homogenization method. The size, PDI, ZP, assay, in vitro release and morphology of OM-NS were characterized. Further, the pharmacokinetic (PK) behavior of OM-NS was evaluated in male wistar rats. Statistically optimized OM-NS formulation exhibited mean particle size of 492 nm, ZP of -27.9 mV and 99.29% release in 5 min. OM-NS showed more than four times increase in its solubility than pure OM. DSC and XRD analyses indicated that the drug incorporated into OM-NS was in amorphous form. The morphology of OM-NS was found to be nearly spherical with high dispersity by scanning electron microscopic studies. The PK results showed that OM lyophilized nanosuspension (NS) exhibited improved PK properties compared to coarse powder suspension and marketed tablet powder suspension (TS). Oral bioavailability of lyophilized NS was increased by 2.45 and 2.25 folds when compared to marketed TS and coarse powder suspension, respectively. Results of this study lead to conclusion that NS approach was effective in preparing OM formulations with enhanced dissolution and improved oral bioavailability.

Nanostructured lipid carriers of olmesartan medoxomil with enhanced oral bioavailability.

The current study explores the potential of nanostructured lipid carriers (NLCs) for oral bioavailability enhancement of olmesartan medoxomil (OLM) by systemic design approach. OLM-NLC was successfully prepared with optimized process parameters (i.e. amount of liquid lipid, total amount of lipid, drug content and surfactant concentration) using the Box-Behnken design of experiments for different response parameters (i.e. particle size, Polydispersity index and entrapment efficiency). Further, optimized formulation was validated which depicted nano size, homogenous distribution with optimum entrapment efficiency. OLM-NLC was characterized by different techniques viz. differential scanning calorimetry (DSC), powder X-Ray diffraction (PXRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), which showed reduced crystallinity of the drug with smooth spherical appearance of nanoparticles. Formulation was found to be stable in simulated gastric fluids as no significant changes were found in size, PDI and entrapment efficiency. In vitro release showed extended release of OLM from OLM-NLC. In vitro cellular uptake study revealed 5.2 folds higher uptake of nanoparticles as compare to the free drug, when incubated with Caco-2 cells. In vivo performance showed that AUCtotal and Cmax of OLM-NLC were found significantly (P<0.01) higher as compare to the free drug. Overall, the present study successfully reports the improvement of oral bioavailability of olmesartan medoxomil.

Formulation, optimization, and in vitro-in vivo evaluation of olmesartan medoxomil nanocrystals.

The aim of the present study is to increase the saturation solubility and oral bioavailability of olmesartan medoxomil (OLM) using nano-sized crystals produced using a combination of antisolvent precipitation and high-shear homogenization. A response surface design comprising 46 runs was used to optimize the OLM nanocrystal formulation. The optimized formulation was produced using a combination of D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) (0.7% w/v), Pluronic F-68® (0.5% w/v), and drug concentration (0.2% w/v) and subjected to 10 and 15 homogenization cycles at 1000 and 1700 bar, respectively. The particle size, polydispersity index (PDI), and zeta potential of optimized formulation were found to be 140 ± 10.34 nm, 0.07 ± 0.016, and -21.43 ± 2.33 mV, respectively. The optimized formulation exhibited irregular morphology as evaluated by scanning electron microscopy and was crystalline as determined by thermal analysis and powder X-ray diffraction studies. OLM nanocrystals showed a marked increase in the saturation solubility as well as rapid dissolution rate in comparison with the pure drug. No significant change in the particle size, PDI, and zeta potential was observed when optimized formulation was stored at room and refrigeration conditions for 3 months. Lastly, in vivo pharmacokinetic studies in Sprague-Dawley rats substantiate the ability of OLM nanocrystal formulation to significantly improve (∼4.6-fold) the oral bioavailability of OLM in comparison with the free drug. This study has established a potential and commercial viable OLM formulation with enhanced saturation solubility and in vivo oral bioavailability.

Solid lipid nanoparticles as vesicles for oral delivery of olmesartan medoxomil: formulation, optimization and in vivo evaluation.

OBJECTIVE: Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability (28%) resulting from poor aqueous solubility, presystemic metabolism and P-glycoprotein mediated efflux. The present investigation studies the role of lipid nanocarriers in enhancing the OLM bioavailability through oral delivery. MATERIALS AND METHODS: Solid lipid nanoparticles (SLN) were prepared by solvent emulsion-evaporation method. Statistical tools like regression analysis and Pareto charts were used to detect the important factors effecting the formulations. Formulation and process parameters were then optimized using mean effect plot and contour plots. The formulations were characterized for particle size, size distribution, surface charge, percentage of drug entrapped in nanoparticles, drug-excipients interactions, powder X-ray diffraction analysis and drug release in vitro. RESULTS AND DISCUSSION: The optimized formulation comprised glyceryl monostearate, soya phosphatidylcholine and Tween 80 as lipid, co-emulsifier and surfactant, respectively, with an average particle size of 100 nm, PDI 0.291, zeta potential of -23.4 mV and 78% entrapment efficiency. Pharmacokinetic evaluation in male Sprague Dawley rats revealed 2.32-fold enhancement in relative bioavailability of drug from SLN when compared to that of OLM plain drug on oral administration. CONCLUSION: In conclusion, SLN show promising approaches as a vehicle for oral delivery of drugs like OLM.

Azilsartan in Patients With Mild to Moderate Hypertension Using Clinic and Ambulatory Blood Pressure Measurements.

This was a phase 2, multicenter, randomized, parallel-group, double-blind dose-ranging study. Hypertensive adults (n=555) received one of five doses of azilsartan (AZL; 2.5, 5, 10, 20, 40 mg), olmesartan medoxomil (OLM) 20 mg, or placebo once daily. The primary endpoint was change in trough clinic diastolic blood pressure (DBP) at week 8. Compared with placebo, all AZL doses (except 2.5 mg) provided statistically and clinically significant reductions in DBP and systolic blood pressure (SBP) based on both clinic blood pressure (BP) and 24-hour ambulatory BP monitoring (ABPM). AZL 40 mg was statistically superior vs OLM. Clinic BP was associated with a pronounced placebo effect (-6 mm Hg), whereas this was negligible with ABPM (±0.5 mm Hg). Adverse event frequency was similar in the AZL and placebo groups. Based on these and other findings, subsequent trials investigated the commercial AZL medoxomil tablet at doses 20 to 80 mg/d using 24-hour ABPM.